Nonhuman Primates as Models of the Menstrual Cycle

Thomas Hope of Northwestern University started today’s meeting with a talk about his studies of how fluorescently labeled HIV particles enter the mucosal barrier of the macaque reproductive tract. One important topic is to study if and how the menstrual cycle affects this process, Hope said. “[This is] becoming an interesting and important topic that many groups need to consider in prevention science and pathogenesis and transmission,” he said.

Hope studied viral entry into the vagina of macaques that had been treated with Depo-Provera, a contraceptive that mimicks the luteal phase of the menstrual cycle by thinning the vaginal mucosa and has recently been shown to double the susceptibility to HIV infection in women (Lancet Infect. Dis. 2011; doi:10.1016/S1473-3099(11)70247-X). He found that in Depo-Provera treated animals, more T cells came close to the surface, possibly explaining why Depo-Provera increases transmission.

Hope has also been studying virus penetration in pigtail macaques at different points of the menstrual cycle. While the study is still blinded, there is considerable variation, similar to the difference between animals that were treated with Depo-Provera and untreated animals, Hope said.

Differences in the menstrual cycle can likely also change the efficacy of vaginal gels containing the antiretroviral tenofovir (TFV), according to Charles Dobard of the US Centers for Disease Control and Prevention (CDC). Dobard reported today that in pigtail macaques, the concentration of a metabolite of TFV in vaginal lymphocytes was about five times higher during the luteal phase (when the vaginal epithelium is thinnest and the susceptibility to infection is highest) than in the follicular phase of the menstrual cycle; the TFV levels in plasma were also higher in the luteal phase.

This suggests that TFV absorption is highest during the luteal phase. “The good thing is that we see more absorption when there is more thinning [of the epithelium], so with the higher susceptibility to infection there is also more drug going in,” said Walid Heneine of the CDC who led the study, adding that knowledge of how absorption of antiretrovirals changes during the menstrual cycle is important to interpret the results of clinical trials of microbicides that use antiretroviral drugs, such as the recent CAPRISA 004 trial, which showed for the first time that a microbicide gel containing 1% TDF was able to reduce HIV incidence by 39% in a group of South African women. Most of the women in that trial were on Depo-Provera, Heneine said. “You would think that they were absorbing the drug very well vaginally,” Heneine said, adding that the variation in the uptake of ARVs during the menstrual cycle in women is not known. “We have to see to what extent this happens in women.”